Comparison of visfatin levels in patients with breast cancer and endometrial cancer with healthy individuals: A systematic review and meta‐analysis

Abstract Background and aims Endometrial cancer (EC) and breast cancer (BC) are prevalent in women. Visfatin is an adipokine that, in addition to being involved in metabolism and inflammation, may also be interested in carcinogenesis. Visfatin measurement in cancer patients has shown that visfatin levels in cancer patients differed from those in healthy subjects. Various studies have shown that the level of visfatin is increased in people within EC and BC, and this difference has a significant relationship with prognosis. Methods A comprehensive search of related articles from PubMed, Scopus, Web of Science, and the Google Scholar database was done by November 2021. Eligible articles measured visfatin levels in patients with breast cancer and EC. After selecting the eligible studies, the data were extracted and analyzed using the random effect method. Results Given the effect size and the confidence interval obtained, the total level of visfatin in cancer patients was different from that in healthy individuals, and this difference was statistically significant. However, the difference in visfatin levels in patients with breast cancer was much more significant than in patients with EC compared to the control group. Conclusions Due to the significant increase in visfatin levels in these patients, visfatin may be a potential prognostic factor in breast and ECs. Visfatin levels in cancer patients differed from those in healthy subjects, and this difference was also statistically significant (p‐values = 0.00). Visfatin levels also differed between breast cancer patients and healthy individuals, which was statistically significant (p‐values = 0.00). The difference in visfatin levels between patients with EC and healthy subjects was statistically significant (p‐values = 0.047).


| INTRODUCTION
Breast cancer (BC) is one of the most widespread kinds of nonskin malignant neoplasm, showing a growing incidence worldwide. [1][2][3] generally begins with ductal hyperproliferation and develops into benign tumors and/or metastatic carcinomas upon constantly being stimulated by different carcinogenic factors. 4 This cancer is associated with age, genetic history, hormonal status, lifestyle, and obesity. 1,5,6 Furthermore, adipocyte-secreted hormones play a substantial role in developing this cancer. 7 Endometrial cancer (EC) is the most prevalent gynecologic malignancy. 8 In postmenopausal women, abnormal uterine bleeding is usually associated with EC. 9 Metabolic disorders, inflammation, impaired immunity, obesity, and hypertension are considerable risk factors. 2 Evaluation of endometrial biopsies, endometrial curettage, and hysterectomy specimen can facilitate disease diagnosis. 9 Postmenopausal women with a mean age of 68 are patients mostly diagnosed with EC. In recent years, the prevalence of EC has been increasing. 10 Adipose tissue, as an endocrine organ, is involved in immunity and homeostasis. 3 This tissue secretes adipocytokines such as visfatin, resistin, and leptin, which may be helpful in the prognosis and diagnosis of cancer, 2,3,11 which can be beneficial for cancer prognosis and diagnosis. 11 Visfatin was identified in 2005. It is a large 52 kDa protein, with its gene being located on chromosome 7q22.2. 2 Visfatin is recognized as pre-B-cell colony-enhancing factor 1 (PBEF1) or nicotinamide phosphoribosyl-transferase (NAMPT). 12 Tumor epithelial cells secrete visfatin autocrinally. Visfatin affects both normal and neoplastic mammary tissues by endocrine and paracrine mechanisms. 1 It involves various metabolic pathways within mammalian cells, such as oxidation of fatty acids, growth, apoptosis, and angiogenesis. 12,13 Some investigations have also reported on its inflammatory effects. 3 Altered serum visfatin levels are associated with different cancers, including breast, endometrial, gastric, and colon. 13,14 Therefore, it seems that visfatin can be used as a biomarker for cancers.
This study aimed to evaluate the serum concentration of visfatin in patients with EC and patients with BC in comparison with healthy individuals.

| Search strategy
We investigated the available articles in PubMed, Scopus, Web of Science, and the Google Scholar databases until November 2021.
A combination of the following keywords was used in our searches as follows: ("Visfatin" OR Nicotinamide Phosphoribosyltransferase) AND ("BC" or Breast neoplasm) AND ("EC" OR Endometrial Neoplasm).

| Inclusion and exclusion criteria
Articles that measured visfatin levels in patients with breast and EC were included in the study. Review studies, letters, and studies in languages other than English were excluded.

| Study selection and data extraction
The search was conducted by two independent reviewers (Ghaneialvar H. and Shiri S.) in duplicate to avoid errors. All articles retrieved by the search strategy based on title and abstract were screened for eligibility. The discrepancies among papers were surmounted by discussion and consensus. Data were collected for each document, including the author's name, year of publication, country, age, the total number of participants, number of healthy controls, number of cases, visfatin level in healthy control, and visfatin levels in patients (Table 1).

| Quality assessment
We assessed the quality of the selected articles using a scoring system based on the modified Newcastle Ottawa Scale (NOS) for case-control studies. Studies that scored five entered the process of meta-analysis (15).

| Statistical analysis
Heterogeneity between studies was assessed using the Q Cochran test and I 2 index. Egger's test was used to evaluate publication bias. Random effects model was used to combine the result of different studies. Data were analyzed using STATA software ver. 11. A p-value less than 0.05 is considered statistically significant.

| RESULTS
Based on the search strategy, we initially retried 227 articles. Then duplicates were removed, and 126 articles remained. In the next step, the title and abstract of the articles were checked, and 74 papers were excluded. The full text of the remaining 52 articles was evaluated, and 42 were removed due to insufficient information.
Finally, 10 articles were included in the meta-analysis, as shown in  Visfatin levels in cancer patients differed from those in healthy subjects, and this difference was also statistically significant (p-values = 0.00). Visfatin levels also differed between BC patients and healthy individuals, which was statistically significant (p-values = 0.00). The difference in visfatin levels between patients with EC and healthy subjects was statistically significant (p-values = 0.047), as shown in Figure 2. However, the difference in visfatin levels in patients with BC was much more significant than in patients with EC compared to the control group. The Eger test examined the symmetry of the funnel diagram ( Figure 3); the p-value was 0.14. We can conclude that the funnel chart is symmetric.
Indeed, these conditions indicated a lack of publication bias ( Figure 3).

| DISCUSSION
In this study, results obtained from the analysis of 10 articles showed Visfatin levels in cancer patients differed from those in healthy subjects. In general, elevated serum visfatin levels in people with BC and EC compared to healthy individuals indicate that visfatin may be a promising biomarker for the early detection of such cancers.
Visfatin is an adipokine that, in addition to being involved in metabolism and inflammation, may also be interested in carcinogenesis. 15,16 Evidence suggests a link between visfatin levels and various cancers. 5,17,18 One study reported that high levels of circulating visfatin increased the risk of cancer, highlighting the importance of visfatin as a biomarker in the early detection of cancer, especially preventable cancer. 19   investigation.

CONFLICT OF INTEREST
The authors declare no conflict of interest. The data supporting this study's findings are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Ethics approval is waived because this report involves no experiment.

TRANSPARENCY STATEMENT
The lead author Ali Khorshidi, Roghayeh Khooz affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.